Meet the first and only extended-release dual-acting local anesthetic

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ZYNRELEF is a synergistic combination of bupivacaine and low-dose meloxicam1

As the first and only extended-release dual-acting local anesthetic, ZYNRELEF is uniquely designed to address the challenges of inflammation at the surgical site and serve as a non-opioid foundation for postoperative pain management.1-5

Understanding postoperative pain

Animation: nerve cell membrane with surgical incision, surrounded by acidic environment from inflammation caused by surgery.
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion
  • Pain begins at the site of injury. When a patient experiences a painful stimulus, an electrical signal is sent from the site of injury to the central nervous system.6,7
  • For this communication between the site of injury and the brain to occur, the voltage-gated sodium ion channels of the local nerve cells open, allowing sodium ions into the cell6,7
  • The rapid influx of sodium ions reverses the polarity inside the cell, causing a pain current to travel along the nerve cell membrane6,7
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion

Local anesthetics can act as the first line of defense against pain

Animation: Un-ionized bupivacaine penetrating and becoming activated inside nerve cell membrane through ionization.
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Positively Charged Hydrogen Ion
  • The local anesthetic molecules penetrate the nerve cell membranes7
  • Once inside the nerve cell, they become activated through ionization8
  • Now in its active form, the local anesthetic blocks the voltage-gated sodium ion channels, preventing sodium ions from entering and stopping pain signals from propagating along the nerve cell7
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Positively Charged Hydrogen Ion

However, inflammation can prevent local anesthetics from working optimally

Animation: ionized bupivacaine not penetrating nerve cell membrane due to increased local postoperative inflammation acidity.
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion
  • As the inflammatory process unfolds, the wound site becomes increasingly acidic. This acidity causes more local anesthetic molecules to become ionized outside the nerve cell.8,9
  • Ionized local anesthetic molecules cannot penetrate the nerve cell membrane. Therefore, they are unable to block the sodium ion channels and cannot stop the pain signals from propagating at the surgical site and traveling to the brain.8,9
  • Inflammation reaches its peak around 24 hours following surgery but remains high through the first 72 hours and is one important reason why long-acting local anesthetics have often been limited beyond 24 hours following surgery7-14
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion

ZYNRELEF works to overcome the challenges of inflammation

Animation: The meloxicam in ZYNRELEF is thought to allow more bupivacaine to penetrate nerve cell membrane.
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion
Biochronomer®
Meloxicam
  • The first and only extended-release dual-acting local anesthetic (DALA) is uniquely designed to overcome the challenges of the inflammatory process at the surgical site in order to manage pain through the first 72 hours following surgery1-5
  • ZYNRELEF has a synergistic mechanism of action that combines the local anesthetic bupivacaine with a low dose of the NSAID meloxicam1
  • By mitigating the effects of inflammation, the meloxicam in ZYNRELEF is thought to reduce the acidotic effect of inflammation and normalize the pH at the surgical site1,5
  • This allows considerably more bupivacaine molecules to remain un-ionized outside of the cell, free to penetrate the cell membrane and block the voltage-gated sodium ion channel. This leads to demonstrated improvements in efficacy.1-5
Un-ionized Bupivacaine
Ionized Bupivacaine
Sodium Ion
Acidic Metabolite
Positively Charged Hydrogen Ion
Biochronomer®
Meloxicam

Extended-release Biochronomer polymer technology

Biochronomer with active ingredients, meloxicam and un-ionized bupivacaine.
Un-ionized Bupivacaine
Meloxicam
Biochronomer

ZYNRELEF is delivered in a proprietary extended-release Biochronomer polymer that provides controlled diffusion of the active ingredients at the surgical site to enable sustained, consistently regulated delivery over the course of 72 hours.1,5

ZYNRELEF is a fixed-dose combination of bupivacaine and low-dose meloxicam. The ratio of bupivacaine to meloxicam is 33:1.1 As the active components are released from the formulation, the polymer hydrolyzes into benign, water-soluble end products, which are eliminated from the body.5

The Biochronomer polymer technology is in a product that has been used more than 300,000 timesa for chemotherapy-induced nausea and vomiting (CINV) patients; it has been applied in more than 50,000 ZYNRELEF patients.1,15-18,b

No mixing with bupivacaine is required to achieve efficacy with ZYNRELEF. The meloxicam in ZYNRELEF potentiates the effects of bupivacaine over 72 hours without needing support from additional products. It should be applied as is, without diluting or mixing with water, saline, or other local anesthetics. When ZYNRELEF comes in contact with moisture in the tissues, it becomes more viscous, allowing it to stay in place and deliver the active ingredients for the first 72 hours after surgery. Because no mixing with bupivacaine is required to achieve efficacy, there is no risk of calculation error.1

Due to the novel properties of the Biochronomer polymer, other local anesthetics can be administered before ZYNRELEF without causing release of the active ingredients all at once. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF.1

Un-ionized Bupivacaine
Meloxicam
Biochronomer

aBased on units distributed.
bCombined prescription and clinical trial data.
CINV: chemotherapy-induced nausea and vomiting.

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Important Safety Information and Indication

Indication

ZYNRELEF is indicated in adults for instillation to produce postsurgical analgesia for up to 72 hours after soft tissue and orthopedic procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures.

Important Safety Information

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Contraindications

ZYNRELEF is contraindicated in patients with a known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDS have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing CABG.

Warnings and Precautions

Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF. When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours.

Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient.

Hypertension: Patients taking some antihypertensive medication may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.

Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal failure.

Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

Risk of Joint Cartilage Necrosis and Degeneration with Unapproved Intra-articular Use: Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration.

Chondrolysis: Limit exposure to articular cartilage due to the potential risk of chondrolysis.

Methemoglobinemia: Cases have been reported with local anesthetic use.

Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically.

Fetal Toxicity: Due to the risk of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus with NSAIDS, limit use of ZYNRELEF between about 20 to 30 weeks gestation, and avoid use after about 30 weeks.

Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia.

Drug Interactions

Drugs That Interfere with Hemostasis: Monitor patients for bleeding who are using ZYNRELEF with drugs that interfere with hemostasis (eg, warfarin, aspirin, SSRIs/SNRIs). 

ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

Use in Specific Populations

Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving.

Severe Hepatic Impairment: Only use if benefits are expected to outweigh risks; monitor for signs of worsening liver function.

Severe Renal Impairment: Not recommended.

Adverse Reactions

Most common adverse reactions (incidence ≥5%) in controlled clinical trials with ZYNRELEF are soft tissue procedures: vomiting and orthopedic procedures: constipation and headache.

Report side effects to Heron at 1-844-437-6611 or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

ZYNRELEF is indicated in adults for instillation to produce postsurgical analgesia for up to 72 hours after soft tissue and orthopedic procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures.

Please see full Prescribing Information, including Boxed Warning.

References: 1. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2024. 2. Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee G-C. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: Phase III results from the randomized EPOCH 1 study. Reg Anesth Pain Med. 2019;44(7):700-706. doi:10.1136/rapm-2019-100531. 3. Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the Phase 3 EPOCH 2 study. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6. 4. Lachiewicz PF, Lee G-C, Pollak R, Leiman D, Hu J, Sah A. HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044. 5. Ottoboni T, Quart B, Pawasauskas J, Dasta JF, Pollak RA, Viscusi ER. Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain. Reg Anesth Pain Med. 2020;45(2):117-123. doi:10.1136/rapm-2019-100714. 6. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451. doi:10.7326/0003-4819-140-8-200404200-00010. 7. Berde CB, Strichartz GR. Local anesthetics. In: Miller RD, Cohen NH, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, eds. Miller’s Anesthesia. Vol 1. 8th ed. Philadelphia, PA: Saunders; 2015:1028-1054.e4. 8. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98-109. doi:10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2. 9. Hargreaves KM, Keiser K. Local anesthetic failure in endodontics: mechanisms and management. Endod Topics. 2002;1(1):26-39. doi:10.1034/j.1601-1546.2002.10103.x. 10. Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2008;26(2):31-37. doi:10.1016/j.mpsur.2007.11.005. 11. Kim J, Burke SM, Kryzanski JT, et al. The role of liposomal bupivacaine in reduction of postoperative pain after transforaminal lumbar interbody fusion: a clinical study. World Neurosurg. 2016;91:460-467. doi:10.1016/j.wneu.2016.04.058. 12. Data on file. DRG physician survey. San Diego, CA: Heron Therapeutics Inc; 2017. 13. Ali A, Sundberg M, Hansson U, Malmvik J, Flivik G. Doubtful effect of continuous intraarticular analgesia after total knee arthroplasty: a randomized, double-blind study of 200 patients. Acta Orthop. 2015;86(3):373-377. doi:10.3109/17453674.2014.991629. 14. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals Inc; 2021. 15. Data on file. SUSTOL periodic safety update report 07. San Diego, CA: Heron Therapeutics Inc; 2020. 16. Data on file. ZYNRELEF periodic safety update report 01. San Diego, CA: Heron Therapeutics Inc; 2021. 17. Data on file. ZYNRELEF periodic benefit-risk evaluation report 02. San Diego, CA: Heron Therapeutics Inc; 2021. 18. Data on file. Combined prescription and clinical trial data. San Diego, CA: Heron Therapeutics Inc; 2022.